Seasonal Affective Disorder (SAD) is one of the most common mood disorders, affecting 1-3% of the population in temperate climates, predominantly women. Currently, there are no specific drug therapies for SAD. Patients are prescribed general anti-depressants or bright light therapy. SAD symptoms include low mood, loss of interest, difficulty concentrating, loss of energy and fatigue. In addition, SAD patients tend to have an increased appetite with associated weight gain and carbohydrate cravings, sweets in particular, in the afternoon or evening. There is often an intense daytime drowsiness in spite of increased sleep duration. SAD constitutes an unmet medical need. The prevalence of SAD and the absence of specific, efficacious and safe pharmacotherapy warrant initiation of a project to discover a therapeutic based in the biology the disease. The end goal of the proposed work is the development a pharmaceutical treatment for SAD by targeting the melanopsin-expressing, intrinsically photosensitive retinal ganglion cells (ipRGC) found in the mammalian retina. The pathway is biologically validated in that bright light therapy, which stimulates the ipRGCs, is efficacious in patients with SAD, and patients having a particular melanopsin mutation have been found to be ~6x more likely to have SAD. The pathway has at its apex, melanopsin, a G-protein coupled receptor (GPCR) that is only expressed in the target cells. A drug activating melanopsin should be able to entrain and shift the circadian pacemaker in the suprachiasmatic nucleus and thus would be invaluable as a drug to treat SAD, as well as jet lag, insomnia related to shift work, and sleep timing disorders. The proposed Specific Aims are (1) demonstrate luminescence reporter assay readout of activation of human melanopsin in 293T cells;(2) optimize the reporter system in several cell types;(3) identify by microarray analysis other, potentially better, reporters and evaluate their performance in the luminescence assay;and (4) adapt and validate the optimized assay from Aims 1-3 for a high-throughput screen for melanopsin agonists. There is, to our knowledge, no pharmaceutical precedent to this approach. PUBLIC HEALTH RELEVANCE: Millions of Americans suffer from a disease called Seasonal Affective Disorder (SAD). People with SAD exhibit classical symptoms of depression during the winter months, associated with the prolonged periods of darkness as are found in higher latitudes. Increasing evidence points to a disruption of the light-dark cycling that is inherent in humans as the primary cause of SAD. We are developing drugs that target the source of the light-dark cycling;cells in the eye that do not contribute to normal vision but detect whether it is night or day. Our therapy should be better than existing treatments, which are non-specific, as we are targeting the primary source of the disease.